3-indolpyruvic acid has the following formula; ##STR1## and is a ketoacid widely known in the literature since it is present in large quantities in plants and seeds, where it seems to be a growth enhancing agent.
In Japanese Pat. No. 4274 (28 May 1959), the acid is described as an intermediate product in the preparation of tryptophan from 3-indolacetic acid.
It was observed in 1964 that the ketoacid is a normal metabolite of mammalian central nervous systems (J. Biochem., 92, 23P), while subsequent work by Russian researchers showed that the ketoacid can favourably replace tryptophan as a growth enhancer for chickens. There are no reports that 3-indolpyruvic acid has ever been used for therapeutic purposes.
According to the present invention, it has recently been discovered that the ketoacid 3-indolpyruvic acid, administered orally to Sprague Dawley rats, is capable of considerably increasing cerebral serotonin levels, while leaving the cerebral concentrations of the other neurotransmitters practically unaltered, thus returning a pathologically unbalanced system to equilibrium.
Insufficient serotonin at the level of the central nervous system has often been related to the appearance of striking pathological phenomena, such as endogenous depressions, headaches, sleep and appetite disturbances, neuroendocrine imbalances, etc. .Since serotonin cannot cross the hematoencephalic barrier, and so cannot be administered as a drug, previous techniques involved the administration of its precursors, in order to increase cerebral levels.
L-tryptophan has been used in the Anglo-Saxon world for many years to treat insomnia and depressions, more recently, France and Italy have approved the use of 5-hydroxytryptophan to treat depressions and all other pathology related to the lack of cerebral serotonin.
Tryptophan, however, presents striking problems as a precursor of cerebral serotonin, since it is to a great degree degraded at the hepatic level by tryptophan pyrrolase toward the quinurenin cycle, itsis captured by the plasma proteins giving rise to unpredictable levels of the free aminoacid, and finally it competes with all the other neutral aminoacids for passage through the hematoencephalic barrier, all of which makes it practically impossible to predict its pharmacological effects.
5-hydroxytryptophan, in turn, also competes with the carrier which transports neutral aminoacids into the central nervous system, and may furthermore be decarboxylated to serotonin by catecholaminergic neurons as well, giving rise to possible imbalances in these neurotransmitter pathways also through the formation of false transmitters.
3-Indolpyruvic acid, on the other hand, is not degraded by tryptophan pyrrolase to such a degree, does not compete with the aminoacids for entrance to the central nervous system, and is first transformed to tryptophan, and then to serotonin, only by serotoninergic neurons, which have the enzyme tryptophan hydroxylase. Therefore the ketoacid may be seen as the most advantageous precursor for the biosynthesis of cerebral serotonin. Other considerations of a biochemical nature also lead to the preferred use of ketoacids to antagonize the increase in ammonia resulting from conditions of cellular distress. In fact, if the serotonin insufficiency is due to chronic deficiency of the precursor, it may be predicted that the use of aminoacids will have little effect, while the use of ketoacids would seem more rational since they can restore adequate precursor levels.
With regard to toxicity, there seem to be no problems for therapeutic levels, since administration of 500 mg in a woman caused no undesired effects (J. Nutr. 102, 1547 (1972)).